Solution Structures of UBA Domains Reveal a Conserved Hydrophobic Surface for Protein–Protein Interactions

Mueller, Thomas D.; Feigon, Juli

doi:10.1016/s0022-2836(02)00302-9

Cited by 166 publications

(220 citation statements)

References 35 publications

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“…1). Structures have been previously solved for each of the UBA domains of hHR23a when expressed as single domain constructs (35,36). We found that these structures are preserved in the context of full-length hHR23a, as their backbone rms deviation is within 1.5 Å to their respective structures in the 40-kDa protein.…”

Section: Hhr23a Contains Four Structural Domainsmentioning

confidence: 80%

DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a

Walters

Lech

Goh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

135

165

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The Rad23 family of proteins, including the human homologs hHR23a and hHR23b, stimulates nucleotide excision repair and has been shown to provide a novel link between proteasome-mediated protein degradation and DNA repair. In this work, we illustrate how the proteasomal subunit S5a regulates hHR23a protein structure. By using NMR spectroscopy, we have elucidated the structure and dynamic properties of the 40-kDa hHR23a protein and show it to contain four structured domains connected by flexible linker regions. In addition, we reveal that these domains interact in an intramolecular fashion, and by using residual dipolar coupling data in combination with chemical shift perturbation analysis, we present the hHR23a structure. By itself, hHR23a adopts a closed conformation defined by the interaction of an N-terminal ubiquitin-like domain with two ubiquitin-associated domains. Interestingly, binding of the proteasomal subunit S5a disrupts the hHR23a interdomain interactions and thereby causes it to adopt an opened conformation.

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Section: Hhr23a Contains Four Structural Domainsmentioning

confidence: 80%

DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a

Walters

Lech

Goh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

135

165

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“…Construct with a Mutated UBA Domain-To gather a greater understanding of SNF1 kinase regulation and function in yeast, we focused on the role played by the UBA domain, a loose linear sequence present in yeast and mammalian AMPK-related kinase ␣ subunits that fold into a conserved tri-helical structure characterized by a hydrophobic face (48). Such UBA surfaces can associate noncovalently with the globular head of ubiquitin or poly-Ub chains, yet this function has not yet been detected for the AMPK-related kinase class of human proteins (36) nor reported for the yeast ␣ subunit, Snf1 (38).…”

Section: Generation Of a Snf1mentioning

confidence: 99%

The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

Jiao¹,

Postnikoff²,

Harkness³

et al. 2015

Journal of Biological Chemistry

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Background:The UBA domain in the AMP kinase family is poorly defined. Results: This motif restrains kinase activity, resulting in decreased life span and oxidative stress resistance. Conclusion: This inhibitory domain has defined influences with FOXOs on stress and aging. Significance: The overactive kinase created by UBA mutations has positive stress resistance and aging influences that may translate to human metabolic benefits.

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“…The functional motifs in p62 include a Phox and Bem1p domain (PB1) domain that embeds an octicosapeptide Phox, Cdc and the atypical PKC-interaction domain (AID) (OPCA) motif, a ZZ zinc finger, a binding site for Tumor necrosis factor Receptor-Associated Factor 6 (TRAF6), two PEST sequences, and an Ubiquitin-associated (UBA) domain [4]. The Cterminal ubiquitin-associated domain (UBA) was discovered to bind non-covalently to ubiquitin [5]. In vitro binding studies have unveiled p62 as a unique ubiquitin-binding protein, which binds polyubiquitin non-covalently through its C-terminus [6].…”

Section: Introductionmentioning

confidence: 99%

Identification of a consensus site for TRAF6/p62 polyubiquitination

Jadhav

Geetha

Jiang

et al. 2008

Biochemical and Biophysical Research Communications

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Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an ubiquitin ligase that regulates a diverse array of physiological processes via forming Lys-63 linked polyubiquitin chains. In this study, the lysine selection process for TRAF6/p62 ubiquitination was examined. The protein sequence of two characterized TRAF6/p62 substrates, NRIF and TrkA, revealed a conserved consensus pattern for the ubiquitination site of these two TRAF6 substrates. The consensus pattern established in the verified substrates was common to the other Trk receptor family members, TrkB and TrkC. Interestingly, Lysine 811 in TrkB was selected for ubiquination, and mutation of Lysine 811 diminished the formation of TRAF6/p62 complex that is necessary for effective ubiquination. Moreover, downstream signaling was affected upon binding of BDNF to the mutant TrkB receptor. These findings reveal a possible selection process for targeting a specific lysine residue by a single E3 ligase and underscore the role of the scaffold, p62, in this process. KeywordsUbiquitination; Ub ligase; TRAF6; p62; Trk Many adaptors have been identified in studies of other neuronal tyrosine kinases that may also prove to function in Trk receptor-mediated signaling [1]. Cytoplasmic protein p62 was identified as an interacting partner of atypical protein kinase C (PKC) [2] and has been shown to contain several protein-protein interacting modules that enable the protein to serve as a scaffold for activation of the transcription factor NF-κB [3]. The multidomain protein structure of p62 is suggestive of diverse protein-protein interactions and its link in cellular functions. The functional motifs in p62 include a Phox and Bem1p domain (PB1) domain that embeds an octicosapeptide Phox, Cdc and the atypical PKC-interaction domain (AID) (OPCA) motif, a ZZ zinc finger, a binding site for Tumor necrosis factor Receptor-Associated Factor 6 (TRAF6), two PEST sequences, and an Ubiquitin-associated (UBA) domain [4]. The Cterminal ubiquitin-associated domain (UBA) was discovered to bind non-covalently to ubiquitin [5]. In vitro binding studies have unveiled p62 as a unique ubiquitin-binding protein, which binds polyubiquitin non-covalently through its C-terminus [6].Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes. E3 Ub ligases are known to interact with specific substrates either directly or through adaptor proteins. *Corresponding author. Fax: +1 (334) 844-5255, Email address: wootemw@auburn.edu (M. Wooten). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . High substrate specificity of the ...

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Solution Structures of UBA Domains Reveal a Conserved Hydrophobic Surface for Protein–Protein Interactions

Cited by 166 publications

References 35 publications

DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a

DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a

The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

Identification of a consensus site for TRAF6/p62 polyubiquitination

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